Low-risk Acute Myeloid Leukemia Research Articles

Limited efficacy of 3 + 7 plus gemtuzumab ozogamycin in newly diagnosed fit intermediate genetic risk acute myeloid leukemia patients.

Gemtuzumab-ozogamycin (GO) is approved in combination with high-dose chemotherapy for treatment-naïve low- and intermediate-risk acute myeloid leukemia (AML). In this retrospective real-life multicenter study, we reported efficacy and safety of GO plus high-dose chemotherapy in newly diagnosed AML patients. A total of 31 fit low- and intermediate-risk AML patients treated with GO-based regimens were retrospectively included in this real-life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO-based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate-risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02-0.89; p < .001). GO addition resulted in a survival benefit for low-risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate-risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO-treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno-occlusive disease after allogeneic transplantation were observed. Our real-life multicenter study confirmed GO-based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate-risk AML. However, further validation on larger prospective cohorts is required.

Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

Centralized MRD Assessment at Early Timepoints in Gimema AML1718 Trial, a Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk AML

Background: New therapeutic strategies are strongly needed to improve the prognosis of high risk Acute Myeloid Leukemia (AML) patients, such as combination of novel agents and conventional chemotherapy. The Italian GIMEMA AML1718 trial (NCT03455504) investigate the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) in combination with intensive fludarabine-based induction (FLAI) [fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5] as first-line therapy for newly diagnosed non low-risk ELN AML patients. Results from the Planned Interim Analysis of Safety Run-in and Part 1 (early expansion cohorts) were presented at the last 2022 ASH Meeting. Median overall survival (OS) was not reached; probability of 12-month OS was 76%. Median disease-free survival was not reached. With a median follow-up of 10.5 months, 28 patients (49%) received allogeneic stem cell transplantation (HSCT) in first complete remission (CR). Centralized multicolour flow cytometry minimal residual disease (MFC-MRD) assessment was planned during the phase 2, part 2 of the study (confirmatory cohort) where the lower effective dose of VEN (400 mg/day) was administered in association with FLAI. Here we report results from early time-points (TPs) MRD analysis with the aim of identify the most informative TPs for MRD assessment and prognostic correlations. Methods: Erythrocyte-lysed whole bone marrow (BM) samples obtained at diagnosis from patients enrolled in the confirmatory cohort were centralized and analysed with a broad panel of monoclonal antibodies to identify the leukemia-associated phenotype (LAIP) which was used to track residual leukemic cells during follow-up. Eight color flow cytometry analysis was performed at pre-defined TPs (TP1: post-induction I, TP2: post induction II/consolidation I, following TPs: post consolidation/pre-transplantation) (FACSCantoII; BD Facs Diva Software V6.1.3). A positive flow MRD was defined by the presence of no less than 10 clustered leukemic cells/10^4 total events. Enrollment closed on January 2023. Collection and analysis of later TPs is ongoing. Results: Sixty-seven patients from 11 centers were enrolled in the phase 2, part 2. Risk stratification according to ELN 2017 was intermediate in 46% of patients and high risk in 54%. Fifty-eight/67 patients (87%) obtained CR after induction I. In the centralized MRD analysis, 170 samples has been collected and analysed so far (60 baseline samples, 110 MRD samples). Seven patients lacking baseline sample for LAIP identification were excluded from the analysis. TP1 was available in 57/59 patient achieving CR (97%), and TP2 was available in 29 patients, so far. MFC-MRD negativity was obtained in 31/57 (54%) at TP1 (post V-FLAI, Fig. 1). An increase in MFC-MRD negativity rate was observed at TP2 (post Induction II or consolidation I) with 20 MFC-MRD negative patients/29 available samples (69%, Fig. 1). Thirteen/110 follow up samples (8%), albeit resulting MRD negative, were considered inadequate for the analysis due to haemodilution, 9 from TP1 and 4 from TP2 (Fig. 1). TP1 and TP2 MRD assessment were scheduled at day 28 of Induction I and Induction II/consolidation, respectively. However, in most cases, delayed haematological recovery was observed after V-FLAI, thus resulting in suboptimal samples for MRD evaluation. Conclusions: Preliminary results from centralized MRD analysis confirm that the combination therapy is able to induce high-quality remissions with a very high percentage of MFC-MRD negativity in a difficult cohort of patients, with a higher percentage of MFC-MRD-negative after the completion of the second course of therapy. Delayed haematological recovery may impact on reliability of MRD assessment due to hypocellular and regenerative marrow samples, suggesting that in those cases MRD analysis should be postponed. Correlation with survival will be performed as the data collection will be complete.

The Efficacy of Modified Melphalan and Busulfan-Based Conditioning Regimen for Autologous-HSCT in Low-Risk and Intermediate-Risk AML Patients

Abstract: Background: Treatment options for patients with low-risk and intermediate-risk acute myeloid leukemia (AML) patients (non-M3) who achieved complete response (CR) after one course of induction chemotherapy include consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Compared with chemotherapy, auto-HSCT could significantly reduce relapse rate, as was associated with significantly lower transplant-related mortality compared with allo-HSCT, but relapse rate was relatively high. The selection of conditioning regimen was crucial to reduce relapse rate after transplantation. In this study, we made refinements in the conditioning regimen with two alkylating agents, namely MCBA (the combination of melphalan, cladribine, busulfan, and cytarabine). We aim to investigate the efficacy of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. Methods: This prospective multi-center clinical trial was conducted in 5 tertiary hospitals in China, and enrolled low-risk and intermediate-risk AML patients (non-M3) who achieved CR after one course of induction chemotherapy, followed by 1-3 courses of high-dose cytarabine consolidation chemotherapy, and underwent auto-HSCT from May 2021 to June 2023 (ChiCTR Registration ID: ChiCTR2200056167). The MCBA conditioning regimen consists of melphalan 70mg/m 2/d, day -6~-5, cladribine 5mg/m 2/d, day -4~-2, busulfan 3.2mg/kg/d, day -8~-7, cytarabine 2g/m 2/d, day -4~-2. Results and Discussion: This study included a total 21 AML patients, 14 males, 7 females, with median age 41 years (ranged 20-56 years). There were 8 of low-risk and 13 of intermediate-risk. The median infused mononuclear cell and CD34+ cell counts were 12.22×10 8/kg (ranged 1.79-34.68×10 8/kg) and 2.28×10 6/kg (ranged 1.05-17.15×10 6/kg) respectively. Neutrophil and platelet engraftment were achieved in all patients, with a median time of 13 days (ranged 11-27 days) and 32 days (ranged 12-150 days) respectively. On the day of reconstitution, all patients exhibited good responses, including hematologic CR and minimal residual disease (MRD) negativity rates of 100%. 11 (52.4%) patients received maintenance therapy after auto-HSCT, with a median time of 3.5 months (ranged 1-9 months). Azacytidine, venetoclax or geritinib were the main maintenance therapies. With a median follow-up of 306 days（ranged 43-798 days）, the estimated 1-year overall survival (OS) and 1-year disease-free survival (DFS) were 80.4±13.4% and 70.9±12.8%, respectively. 4 patients relapsed within 1year, and the median time from HSCT to relapse was 240 (101-314) days. The probability of relapsed rate was 29.1±12.8%. Mucositis was the main reported regimen-related toxicity, mostly were mild and well tolerated. Severe mucositis included grade Ⅱ liver damage (4.8%), grade Ⅱ oral mucositis (4.8%) and grade Ⅲ-Ⅳ diarrhea (9.5%), respectively. Conclusion: The preliminary data demonstrated the efficiency of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. The regimen-related toxicity was well tolerated.

Optimal Duration of CPX-351 Treatment and Best Timing for Consolidation with Allogeneic Stem Cell Transplantation: Evidence from a Large Real-World Italian Study

Background: CPX-351, has been approved for the treatment of patients diagnosed with Acute Myeloid Leukemia (AML) arising from a previous myelodysplastic syndrome (s-AML) or secondary to chemotherapy (t-AML) as per former WHO 2016 classification, following results from the phase III trial (Lancet et al, JCO2018). Long term results from the trial confirmed that the benefit from CPX-351 over conventional 3+7 induction was maintained both in patients proceeding or not to allogeneic stem cell transplantation consolidation (HSCT). However, the information on the optimal duration of treatment with CPX-351 or the best timing for HSCT consolidation are still incomplete. Furthermore, there is also scarce data on the efficacy of CPX-351 among NPM1 or FLT3-ITD mutated AML or in patient with low risk AML according to European Leukemia Net (ELN) classification, as those subgroups are rare among t-AML and s-AML. Aims: The aim of this study is to analyze the outcome of CPX-351 treatment in a large cohort of patient who received commercially available treatment in Italy since the approval of the drug, in order to identify the optimal duration of treatment, the best timing for HSCT and to evaluate the efficacy among more rare secondary AML subtypes. Methods: 513 elderly (median age 65.6 years, range 19-79) s-AML or t-AML patients who received CPX-351 treatment in 38 Italian Centers since January 2019 were retrospectively included in this study. All patients received CPX-351 as per Italian Drug Authority (AIFA) approval, allowing up to two induction cycles and up to two consolidation. Diagnostic workup was performed as per internal standard in all patients. Eligible patients proceeded to HSCT consolidation as per internal standard of each Center. 108 (21.1%) and 405 (78.9%) patients were diagnosed with t-AML or s-AML, respectively. NPM1 mutation were found in 31 patients (6%), FLT3-ITD mutation was present in 24 patients (4.6%). ELN 2017 score was favorable, intermediate or high in 27 (5.2%), 177 (34.5%) and 309 (60.3%) patients, respectively. Most patients had relevant comorbidities (84%), mainly cardiovascular disease (43%), type II diabetes (39%). After induction 1, 297/513 patients (58%) achieved a complete remission (CR). 72 patients failing to achieve CR received induction 2. After induction 2, CR was achieved in 340/513 patients (66.3%). CR rate was significantly higher among NPM1 mutated patients (p &amp;lt;0.05) and among ELN 2017 favorable risk patients if compared to intermediate or high risk (p&amp;lt;0.05), whereas was not affected by FLT3-ITD mutations. Among responding patients, 118 (34.7%), 137 (40.3%) and 85 (25%) received none, one or two consolidation cycles, respectively. HSCT consolidation in first CR was performed in 166/340 responding patients (48.8%). 30 and 60-days mortality were 5.2 and 8.2%, respectively. After a median follow-up of 23.66 months (CI 95% 23.11 - 26.01), median OS was 16.23 months (CI 95% 13.6 - 18.9). OS was significantly influenced by NPM1 mutational status (p&amp;lt;0.05) and ELN 2017 risk score (p&amp;lt;0.05, Fig. 1A). Of note, NPM1 mutated patients and ELN 2017 low-risk patients showed a very good outcome (Median OS 24.6 months for NPM1 mutated patients and not reached in ELN 2017 favorable risk patients). In a landmark analysis including patients alive and in CR at day 90, HSCT was the strongest predictor of longer survival (Median OS not reached and 16.3 months for patients receiving or not HSCT, respectively, p&amp;lt;0.05). In the same landmark model, completion of all allowed CPX-351 treatment was beneficial only in patients not proceeding to HSCT (median OS 20.36 and 12.2 months in patients receiving 2 or less CPX-351 consolidation without HSCT, respectively, p&amp;lt;0.05, Fig. 1B), whereas in patients receiving HSCT consolidation further CPX-351 treatment after cycle 1 did not improve results (Median OS not reached, 35 and 28.4 months in HSCT patients receiving 0, 1 or 2 CPX-351 consolidations, respectively, p=n.s.) Conclusions: Our large cohort confirms the efficacy of CPX-351 treatment and suggests that CPX-351 may be beneficial also in NPM1 mutated and ELN 2017 favorable risk patients. In eligible patients, HSCT should probably be performed as soon as a CR is achieved, whereas patients not proceeding to HSCT may still have a long survival if two consolidations are administered. In a future perspective, maintenance strategies may further improve the results.

Expression signature of ten small nuclear RNAs serves as novel biomarker for prognosis prediction of acute myeloid leukemia

This study aimed to screen for small nuclear RNAs (snRNAs) associated with the prognosis of acute myeloid leukemia (AML) by using The Cancer Genome Atlas (TCGA) whole-transcriptome sequencing dataset. A total of 130 AML patients from TCGA cohort with complete prognostic information and transcriptome data were enrolled in the current study. Comprehensive survival and functional enrichment analyses were performed to explore the prognostic value and potential biological functions of prognostic snRNAs in AML patients. In the current study, we screened 72 snRNAs that were notably associated with the clinical outcome of AML and developed an expression signature consist of ten snRNAs, that can be accurately applied to assess the overall survival of AML patients. Functional mechanism analysis revealed that this expression signature may be strongly linked to some classical tumor-associated pathways, such as Notch and Wnt pathways, as well as being closely related to B and T cell receptor pathways. Furthermore, we screened six compounds (chicago sky blue 6 B, 5230742, clorsulon, nefopam, nicardipine, and streptomycin) that may serve as targeted therapeutic drugs for AML using connectivity maps. Tumor immunoassays indicated significant differences in the immune microenvironment of the bone marrow tissue between high-risk and low-risk AML patients. Immune infiltration analysis also revealed significant differences in the abundance of multiple immune cells in the bone marrow of the two groups of AML patients groups. In conclusion, our results revealed a novel prognostic expression signature of AML consisting of ten snRNAs, and we conducted a preliminary exploration of its potential biological functions and tumor immunity.

Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to "intermediate" risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.

A Novel Defined Pyroptosis-Related Gene Signature for the Prognosis of Acute Myeloid Leukemia

Pyroptosis is an inflammatory form of programmed necrotic cell death, but its potential prognostic value in acute myeloid leukemia (AML) remains unclear. On the basis of available AML data from TCGA and TARGET databases, a 10-gene signature model was constructed to effectively predict AML prognosis by performing LASSO Cox regression analysis, which showed that patients with a low-risk score had a significantly better prognosis than that of the high-risk group, and receiver operator characteristic (ROC) analysis achieved superior performance in the prognostic model. The model was further well-verified in an external GEO cohort. Multivariable Cox regression analysis showed that, in addition to age, the risk score was an independent poor survival factor for AML patients, and a nomogram model was constructed with high accuracy. Moreover, the high-risk group generally had higher cytolytic activity and increased levels of infiltrating immune cells, including tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs), which could be related to the expression of immune checkpoint genes. Additionally, low-risk AML patients may have a better response from traditional chemotherapeutic drugs. In conclusion, a pyroptosis-related gene signature can independently predict the prognosis of AML patients with sufficient predictive power, and pyroptosis plays an important role in the immune microenvironment of AML, which may be used to develop a new effective therapeutic method for AML in the future.

Gimema AML1718 Part 1: Planned Interim Analysis of a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Gimema AML1718 Part 1: Planned Interim Analysis of a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Effectiveness and Mechanism of Decitabine Maintenance Therapy in Patients with Medium and Low-risk Acute Myeloid Leukemia

To investigate the efficacy and mechanism of decitabine maintenance therapy in patients with medium and low-risk acute myeloid leukemia(AML). The newly diagnosed medium- and low-risk AML patients in the Second Affiliated Hospital of Anhui Medical University from December 2016 to December 2020 were retrospectively analyzed. Seventy-eight AML patients who were still in remission after consolidation treatment were divided into maintenance treatment group (31 cases) and control group (47 cases). The maintenance treatment patients received decitabine at 20 mg/m2 IV daily for 5 days, every three months for 6 cycles, the control group was only observed and tested regularly. Follow-up was completed by telephone or by viewing outpatient or inpatient medical records. Primary indicators were overall survival (OS), and secondary indicators include relapse-free survival (RFS), tolerance, cellular immune function and analysis of risk factors related to survival. Median RFS in maintenance theatment and control groups was 30.1(26.2-33.8) months and 24.3(21.7-30.3) months (P=0.011), median OS 34.7(29.8-39.7) months and 27.7(24.1-31.3) months respectively（P=0.024）, with a statistically significant difference. For the univariate and multivariate Cox regression analysis, only the minimal residual disease (HR=25.185, P<0.001) and the treatment methods (HR=0.124, P<0.001) affected the PFS and OS of patients. In the maintenance treatment group, CD3+T cells, CD8+T cells and NK cells increased significantly after decitabine maintenance treatment, and the regulatory T cells decreased significantly (P<0.05). Patients had a low incidence of grade 3-4 adverse events, hematological adverse events were mainly neutropenia and thrombocytopenia, non-hematological adverse events were mainly digestive tract symptoms, and the patient was well tolerated. Maintenance treatment with decitabine provided benefit survival in patients with medium- and low-risk AML and is well tolerated. The mechanism may be inhibition the proliferation of regulatory T cells, induce and enhance the cytotoxic effect of CD8+ T cells on tumor antigens.

A comparative clinical study of modified IA "3+4" regimen and intermediate-dose cytarabine regimen in the consolidation treatment of low-risk acute myeloid leukemia

A comparative clinical study of modified IA "3+4" regimen and intermediate-dose cytarabine regimen in the consolidation treatment of low-risk acute myeloid leukemia

IL-10 and TNFα are associated with decreased survival in low-risk pediatric acute myeloid leukemia; a children’s oncology group report

Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children’s Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1β were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML.

A novel 4-mRNA signature predicts the overall survival in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive cancer of myeloid cells with high levels of heterogeneity and great variability in prognostic behaviors. Cytogenetic abnormalities and genetic mutations have been widely used in the prognostic stratification of AML to assign patients into different risk categories. Nevertheless, nearly half of AML patients assigned to intermediate risk need more precise prognostic schemes. Here, 336 differentially expressed genes (DEGs) between AML and control samples and 206 genes representing the intratumor heterogeneity of AML were identified. By applying a LASSO Cox regression model, we generated a 4-mRNA prognostic signature comprising KLF9, ENPP4, TUBA4A and CD247. Higher risk scores were significantly associated with shorter overall survival, complex karyotype, and adverse mutations. We then validated the prognostic value of this 4-mRNA signature in two independent cohorts. We also proved that incorporation of the 4-mRNA-based signature in the 2017 European LeukemiaNet (ELN) risk classification could enhance the predictive accuracy of survival in patients with AML. Univariate and multivariate analyses showed that this signature was independent of traditional prognostic factors such as age, WBC count, and unfavorable cytogenetics. Finally, the molecular mechanisms underlying disparate outcomes in high-risk and low-risk AML patients were explored. Therefore, our findings suggest that the 4-mRNA signature refines the risk stratification and prognostic prediction of AML patients.

Simultaneous Identification and Stratification of Low Molecular Risk AML Patients Using a Single LSC17-Based Nanostring Assay at Diagnosis

Refractoriness to induction chemotherapy and relapse after achievement of remission are the main barriers to cure in acute myeloid leukemia (AML). Currently, most AML patients receive standard induction chemotherapy because risk stratification depends on cytogenetic and molecular tests that typically take weeks to return results. We recently reported a rapid 17-gene leukemia stem cell score (LSC17, Ng et al., Nature 2016) that can accurately determine risk within 24 to 48 hours of diagnosis. Patients with high LSC17 scores have poor outcomes with current treatments and could be enrolled in clinical trials evaluating novel upfront treatment strategies.A small subset of AML patients with normal cytogenetics, NPM1 mutation and no FLT3-ITD are classified as low molecular risk (LMR) and are considered to have better outcomes, but ~35% relapse within 2 years following conventional therapy. In our prior study, we derived an optimized, re-weighted sub-score for LMR patients in which only 3 of the 17 genes contribute to the calculated score (LSC3). A high LSC3 score identifies LMR patients who have worse outcomes following standard induction therapy, and who might benefit from novel frontline therapy. Currently however, the LSC3 score can only be employed for risk-adapted therapy decisions in the post-remission setting, as LMR patients are only identified following cytogenetic and molecular testing. Earlier identification of high-risk LMR patients will facilitate clinical trials of novel frontline therapy in this patient subset.To determine whether a subset of the LSC17 signature genes could be used to identify LMR cases at diagnosis, we applied sparse binomial regression to relate the expression of the 17 signature genes to LMR vs. non-LMR cases in a large training cohort comprising AML patients of all subtypes (GSE6891, n=495 patients including 48 [9%] LMR cases). The resulting 13-gene sub-score (LMR13) can accurately identify LMR patients in 6 large independent validation cohorts spanning n=1559 cytogenetically and molecularly diverse AML patients using gene expression data from several different platforms (Figure 1; microarray datasets: GSE37642, n=542, area under the receiver operating characteristic curve (AUROC)=0.88; GSE15434, n=251, AUROC=0.92; TCGA AML, n=183, AUROC=0.92; ALFA-0701, n=192, AUROC=0.89; RNA-Seq dataset: TCGA AML, n=169, AUROC=0.92; NanoString datasets: GSE76004, n=237, AUROC=0.96; PM AML, n=154, AUROC=0.86). Importantly, the LMR13 score for each patient can be calculated from the same NanoString assay used to determine the patient's LSC17 and LSC3 risk scores. The ability to identify LMR cases rapidly at diagnosis enhances the clinical utility of the LSC17 assay, as it will allow clinicians to use the most appropriate risk score (LSC3 vs LSC17) for all newly-diagnosed AML patients, and enable evaluation of novel upfront treatment strategies for higher-risk LMR cases. Furthermore, integration of our functionally defined stem cell gene list with patient survival data using statistical learning approaches provides a basis for ongoing characterization of the molecular pathways associated with clinical outcomes, irrespective of mutational profile. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment of acute myeloid leukemia in children: A practical perspective.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease that requires a multifaceted treatment approach. Although outcomes for low-risk AML have improved significantly over recent decades, high-risk AML continues to be associated with an adverse prognosis. Recent advances in molecular diagnostics, risk stratification, and supportive care have contributed to improvements in outcomes in pediatric AML. Targeted approaches, for example, the use of tyrosine kinase inhibitors to treat FLT3-ITD AML, offer promise and are currently undergoing clinical investigation in pediatric patients. New approaches to hematopoietic stem cell transplantation, including the use of haploidentical donors, are significantly expanding donor options for patients with high-risk AML. This review provides an overview of recent advances in the treatment of pediatric AML that are likely to have clinical impact and reshape the standard of care.

Standardized treatment of low-risk acute myeloid leukemia

根据基因及染色体改变急性髓系白血病可分为低危、中危和高危。低危急性髓系白血病的预后相对较好，复发率低、生存率高，治疗原则与中危、高危急性髓系白血病不同。本文从定义、治疗等方面对低危急性髓系白血病有关内容进行简述。.

Comparative Genomic Analysis of Adolescents and Young Adults Versus Elderly with Acute Myeloid Leukemia

Prognosis and survival outcomes of acute myeloid leukemia (AML) strongly depend on age at diagnosis. In fact, long-term survival rates range from 60% in children and adolescent/young adults (AYA-AML: aged 15-39 years) to 10-15% in elderly patients (E-AML: aged &amp;gt;70 years). The currently available classification and prognostication models incorporate genomic features that include cytogenetics and molecular mutations based on adult AML clinical trials that mainly enroll patients outlying these two age categories. Consequently, prognostication models might still not account for the invariant genomic background of each subgroup. In this study, we aimed to dissect the genomic landscape of AYA-AML and E-AML cases in order to uncover patterns of distinct genomic features of important pathogenetic information, knowing how fundamental it is for the development of novel treatment approaches and more importantly for providing opportunities of individualization therapies. We studied the clinical and genomic characteristics of fully annotated sets of 198 AYA-AML and 414 E-AML cases from the Cleveland Clinic and publicly available data. Median age at diagnosis was 31 years for AYA-AML (range: 16-39 years) and 76 years (range: 71-100 years) for E-AML patients with a significant male preponderance noted in the latter cohort (65% vs 46%, P&amp;lt;0.0001). Based on the 2016 WHO classification, AML subtypes were differently distributed within the two subgroups. Low-risk AML (PML-RARA AML, core-binding factor AML, and CEBPA biallelic AML) was more prevalent among AYA cases while a higher odd of secondary AML (sAML) was found in E-AML. Compared to AYA-AML, E-AML were more typically presenting with a less proliferative disease phenotype, as outlined by a lower bone marrow blast infiltration (median: 34% vs 51%, P=0.04) and a higher frequency of leukopenia at baseline (66% vs 27%, P=0.009). In terms of cytogenetic abnormalities, when compared with AYA-AML, E-AML cases harbored more complex karyotype (32% vs 13%, P=0.002) and other cytogenetic abnormalities e.g., -5/del(5q) (14% vs 2%, P&amp;lt;0.0001), -7/del(7q) (14% vs 5%, P=0.001), -17/del(17p) (5% vs 1%, P=0.02), del(20q) (4% vs &amp;lt;1%, P=0.01) and trisomy 8 (14% vs 5%, P=0.0007) while a significantly lower odd of -9/del(9q) (&amp;lt;1% vs 4%, P=0.006). A total of 1092 somatic mutations were identified by next-generation sequencing of common myeloid genes. The AYA-AML cohort had a total of 249 mutations (ratio 1.25) while 843 mutations were reported in E-AML patients (ratio 2.04). Older patients, as compared to AYA-AML, had more mutations in age-related myeloid genes linked to clonal hematopoiesis, including mutations in DNMT3A (15% vs 6%, P=0.001), ASXL1 (14% vs 4%, P=0.0005), and TET2 (19% vs 7%, P=0.0002). As inferred from the cytogenetic comparisons, TP53 mutations were more frequently detected in E-AML (10% vs 2%, P=0.002) compared to AYA-AML, as they carried more chromosomal 5 and 17 abnormalities which are commonly associated with this genomic lesion. On the other hand, AYA-AML had a higher frequency of mutated WT1 gene (9% vs 2%, P=.0009). Multivariate Cox-Proportional hazard was performed to identify group-specific genomic lesions associated with survival in each cohort. In AYA-AML, normal karyotype (HR:0.59, P=0.02), t(15;17) translocation (HR:0.24, P=0.0001), inv(16)/t(8;21) (HR:0.52, P=0.02) and CEBPA biallelic (HR:0.50, P=0.02) were favorable lesions while complex karyotype had an adverse impact on survival (HR:3.0, P=0.0003). Moreover, while normal karyotype and t(15;17) translocation had a favorable impact in E-AML (HR:0.73, P=0.0001 and HR:0.28, P&amp;lt;0.0001, respectively), mutations in RUNX1 (HR:1.2, P=0.4), TET2 (HR:1.2, P=0.01), and TP53 (HR:1.97, P&amp;lt;0.0001) lead to worse outcomes. In conclusion, we demonstrated that E-AML cases are typically characterized by mutations belonging to the genomic subgroups of DNA methylation and chromatin modifiers, which have been reported to occur in age-related hematopoiesis or CHIP. Moreover, the complexity of aberrations (including cytogenetics) emphasizes that in this group of patients AML arises from a stepwise mutation acquisition model. In contrast, AYA-AML are typically characterized by favorable cytogenetic translocations and less clonal instability, dominated by the enrichment in myeloid leukemia driver gene mutations such as WT1. Disclosures No relevant conflicts of interest to declare.

Prognostic Impact of Extramedullary Infiltration in Pediatric Low-risk Acute Myeloid Leukemia: A Retrospective Single-center Study Over 10 Years

BackgroundThe impact of extramedullary infiltration (EMI) on the clinical outcomes of pediatric patients with acute myeloid leukemia (AML) are controversial. Patients and MethodsA total of 214 pediatric patients with low-risk AML were classified as having EMI (central nervous leukemia [CNSL] and/or myeloid sarcoma [MS]) and not having EMI. Patients with isolated MS before AML diagnosis by bone marrow examination were confirmed with histopathologic examination. For patients diagnosed with AML by bone marrow examination, a thorough physical examination and radiologic imaging were used to confirm MS. ResultsMale gender, a high white blood cell count, the FAB-M5 subtype, t(8;21) and t(1;11) abnormalities, and c-KIT mutations were associated with EMI. The presence of MS was associated with a low complete remission rate (63.6% vs. 79.4%; P = .000) and poor 3-year relapse-free survival (RFS) (62.6% ± 7.5% vs. 87.0% ± 2.8%; P = .000) and 3-year overall survival (73.5% ± 7% vs. 88.8% ± 2.6%; P = .011). Multivariate analysis revealed that MS was a poor prognostic factor for RFS and overall survival. Bone infiltration was an independent risk factor for inferior RFS with MS. Patients with CNSL had a low complete remission rate (58.3% vs. 77.2%; P = .045); however, CNSL did not significantly affect the survival of low-risk patients with AML. ConclusionMS should be considered an independent risk factor to guide stratified treatment.

Interferon-a-2b As a Maintenance Therapy Significantly Improves Disease-Free Survival in Patients with Low-Risk Acute Myeloid Leukemia

Background: Interferon-𝜶has a world-widely acknowledged anti-tumor activity and immunoregulatory function. Rare of the previous study reported significant efficacy of IFN-𝜶in AML (high, medium and low risk) patients. Although cytotoxic chemotherapy significantly improved the survival of low-risk AML, the reported low-risk AML 5-year OS was only 34-65%.Whether Interferon-𝜶-2b(IFN-𝜶-2b) could reduce recurrence and improve DFS in the maintenance therapy of low-risk AML subtypes has not been verified. The aim of this study was to evaluate the efficacy and safety of IFN-𝜶-2b in the maintenance of low-risk acute myeloid leukemia, in order to provide suggestions for clinical practice. Method: This study retrospectively analyzed 31 patients with low-risk AML who were treated with IFN-𝜶-2b maintenance therapy from March 2015 to March 2018 at the Peking University Institute of Hematology. The control group consisted of 1:1 matched 31 patients with low-risk AML. The pairing factors were age, gender, diagnostic time and subtype, induction and consolidation courses, and minimal residual disease (MRD) at the end of chemotherapy. Both groups of patients were AML patients who underwent 1-2 therapeutic induction chemotherapy for complete hematologic remission (CR) and completed 5-7 courses of consolidation chemotherapy. The interferon group was administered with 3 million U ofIFN-𝜶-2b three times a week; the control group was only observed and followed up after consolidation chemotherapy. We compared the treatment efficacy and prognostic improvement in low-risk AML by comparing MRD, disease-free survival (DFS), event-free survival (EFS), and overall survival (OS). Results: The median age of the 31 patients in the interferon group was 50 (21-67) years. Themolecular biological characteristicsof the interferon group were NPM1+/FLT3-ITD-8 cases; CEBPA double mutation 9 cases; CBFβ-MYH11+/C-KIT-5 cases; and ETO+/C-KIT- 9 cases. The median age of the control group was 44 (26-70) years old, and the molecular biological characteristics were paired with the interferon group. The median follow-up time of the 31 patients with low-risk AML in the interferon group and the control group was 14.5 (4-34) months and 16 (5.5-35) months, respectively. The median duration of treatment in the interferon group was 10(1-24) months. In interferongroup, patients with negative or positive MRD status were 16 and 15, respectively. Whereas, in control group, patients with negative or positive MRD status were 20 and 11, respectively. In interferon group, patients with original MRD, 10/15 (66.67%) showed MRD conversion after the median time of 5 (1-14.5) months IFN-𝜶-2b treatment, while in control group 3/11 (27.3%) of the patients showed MRD negative-positive conversion. There was a statistically significant difference in the rate of MRD conversion between the two groups (X2=3.939, P=0.047). The interferon group significantly decreased the rate of MRD compared with the control group. The conversion rate of the interferon group and the control group was (66.67%) vs (27.3%). In addition, the 2-year EFS of the interferon group was significantly higher than that of the control group (81.6±7.5) % vs (50.0±10.9) %, P=0.041(Figure 1.A). With refer to recurrence, 3 patients had hematologic recurrence in the interferon group, compared with 10 in the control group. Each group has 2 persistent MRD positive patients and MRD level increased more than 2 log-fold. 1 patient in control group had negative MRD converted to positive. The 2-year DFS of the interferon group was significantly higher than that of the control group (81.2±8.8)% vs (56.7±9.9)%, P=0.042 (Figure 1.B). There was no significant difference between the interferon group and the control group at 2 years of OS, which was (91.4±5.8)% vs (78.7±10.8)% (P=0.587) (Figure 1.C).In terms of safety, 24/31 (77.4%) had grade 1-2 fever after IFN-𝜶-2b therapy. 4/31 patients (12.9%) developed grade 3-4 hematologic toxicity, all of which were thrombocytopenia. Conclusion:IFN-𝜶-2b as maintenance therapyfor CR1 patients with low-risk AML significantly improved the rate of MRD conversion compared with patients without it. DFS and EFS were higher than those without it. Patients receiving interferon therapy have a low incidence of adverse reactions. Interferon therapy is safe and well-tolerated. Disclosures No relevant conflicts of interest to declare.

High expression of microRNA-500 is associated with poor prognosis in patients with acute myeloid leukemia receiving allogeneic hematopoietic stem cell transplantation.

MicroRNA-500 (miR-500) is a potential prognostic biomarker in a number of different types of cancer, such as prostate cancer and hepatocellular carcinoma. This study aimed to explore the clinical implications of miR-500 expression status in patients with acute myeloid leukemia (AML) that had received allogeneic hematopoietic stem cell transplantation (allo-HSCT). miR-500 expression status and clinical data were obtained from 74 patients with AML in the The Cancer Genome Atlas database receiving allo-HSCT. Patients with low expression level of miR-500 (miR-500low) were significantly more likely to present with a French-American-British classification M2 subtype (P=0.003), and less likely to have the M5 subtype (P=0.040) compared with patients with high expression levels (miR-500high). miR-500low patients were associated with low-risk AML (P=0.003) and core-binding factor subunit b-myosin heavy chain 11 translocation mutation (P=0.021). There was a significant difference in nucleophosmin 1 (P=0.009), NRAS proto-oncogene GTPase/KRAS proto-oncogene GTPase (P=0.047) and PHD finger protein 6 (P=0.040) expression levels between the two groups. miR-500high patients had a decreased overall survival (OS) time compared with the low expression group (P=0.035). Multivariate analysis revealed that miR-500 expression significantly affected OS time independent of other classical prognostic factors, such as age and common mutations. The analysis of survival curves further substantiated this result. The results obtained in the current study suggested that miR-500 may be a suitable prognostic marker for patients with AML receiving allo-HSCT.